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So, I was reading this article about how the FDA is streamlining the process to get new HIV drugs approved for treatment experienced patients who may be running out of treatment options, good news.

However, the article mentions twice how HIV mutates even when someone is effectively treated. It mentions nothing about adherence being a factor and says that even with treatment hiv still mutates. Here's a passage:

Since 1996, the virus has largely been controlled through the use of drug cocktails made up of three or more types of medicines taken together. While these combination therapies limit the number of paths used by the virus to invade human cells, they don’t end its ability to mutate in ways that allow it to overcome the therapies, often within three to four years.

The article is in Bloomberg (not some fly by night outfit). Is it just me or what's up with this?

I didn't see anything wrong with the article. Mutations still occur even when we are adherent to our meds and have an undetectable viral load. Most mutations are not resistant to our meds and effectively killed off. Eventually one of those mutations wins the resistance lottery.

Viral load is akin to the number of lottery tickets HIV has and the length of time we are infected represents the number of lottery drawings. HAART just reduces the number of those resistance lottery tickets out there.

I didn't see anything wrong with the article. Mutations still occur even when we are adherent to our meds and have an undetectable viral load. Most mutations are not resistant to our meds and effectively killed off. Eventually one of those mutations wins the resistance lottery.

Viral load is akin to the number of lottery tickets HIV has and the length of time we are infected represents the number of lottery drawings. HAART just reduces the number of those resistance lottery tickets out there.

Citations, please. Because in my 20 plus years of dealing with HIV/AIDS I haven't ever heard documentation to this (fairly widespread) assertion/myth.

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"Many people, especially in the gay community, turn to oral sex as a safer alternative in the age of AIDS. And with HIV rates rising, people need to remember that oral sex is safer sex. It's a reasonable alternative."

Modern combination therapy is highly effective in reducing the replication of the virus to undetectable levels and in maintaining that suppression. The rate of therapy failure (as determined by viral load becoming detectable) is ∼5% per year.1 Nevertheless, since therapy is required lifelong, a significant minority of patients are likely to develop resistance to at least one class of drugs and it has been shown that the likelihood of failure is greater with second-line therapy.

Resistance arises from mutations and mutations occur randomly all the time in every species. The one we're most familiar with is cancer.

HAART greatly reduces the viral load in our blood but doesn't eliminate it and if it's still there mutations still occur. The presence of a mutation doesn't equate to resistance. My initial genotype tests indicated 5 different genetic variants but I have no resistance to any drugs.

I'm not trying to trivialize this but the the discussion around resistance is largely statistical. Remaining adherent to successful HAART greatly reduces viral load and in the presence of HAART fewer mutations are occurring reducing the odds of one of these being resistant.

Precisely. Future projections are statistical.Nevertheless, since therapy is required lifelong, a significant minority of patients are likely to develop resistance to at least one class of drugs and it has been shown that the likelihood of failure is greater with second-line therapy.

There is NO PROOF of this statement. Its conjecture.

Also, who is included in the study subjects?

What is "a significant minority"?

I see HIV specialist doctors, who are also research professors. The word is, there is no fear of resistance being an issue, these days, if you are adherent.

Bug posted the article because he wondered, it seems to be sloppy, or worse, fear mongering.. Old fears.... Old data. Old experience....

Eventually one of those mutations wins the resistance lottery. Viral load is akin to the number of lottery tickets HIV has and the length of time we are infected represents the number of lottery drawings. HAART just reduces the number of those resistance lottery tickets out there.

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“From each, according to his ability; to each, according to his need” 1875 K Marx

While these combination therapies limit the number of paths used by the virus to invade human cells, they don’t end its ability to mutate in ways that allow it to overcome the therapies, often within three to four years.

People read this and could easily get the impression HIV+ people are doomed. It just makes me sigh. So where are all these people on effective treatment, meaning also all these adherent people, who are having to switch every couple of years because of resistance issues???

Huh, where are they???

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“From each, according to his ability; to each, according to his need” 1875 K Marx

People read this and could easily get the impression HIV+ people are doomed. It just makes me sigh. So where are all these people on effective treatment, meaning also all these adherent people, who are having to switch every couple of years because of resistance issues???

Huh, where are they???

It was not my intent to feed any fear mongering. Merely to state that virilogic failure does still occur in those who are successfully treated with HAART?

There are many reasons to develop new HIV drugs and the need for them for people who have resistance is just one reason. Not the end all.

As with many things about HIV, its complicated and nuanced. But the explanations are too complicated, TMI, and information is dumbed down or glossed over.

Still have 3/4 of the world believing that HAART is battery acid...

The wordings I underlined in bold, are not helping matters. This is boiler plate text in research reports and the texts, those sorts of generalisations, they are there on a different agenda for the article... Shouldn't be misconstrued as fact-based, despite appearing in a scientific article. Shouldn't be misconstrued to apply to everyone living with HIV.

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“From each, according to his ability; to each, according to his need” 1875 K Marx

Last year -- when I was very new to this and reading the literature heavily -- I noted that some of the life expectancy studies are based on assumptions regarding how long each successive therapy regime will be successful. Something like 15-20 years for the first-line regime, 10 years for the second, etc.

When I asked my doc how long I could expect my initial regime to be effective, I basically got a shrug.

Still, the line in the Bloomberg story saying that treatments fail within 3-4 years is obviously baloney, and seems leftover from the early days when the drugs were new and techniques like sequential monotherapy in use. Either that or with severely non-adherent patient groups.

Definitely is and it's not just an issue for those with hiv. It's a global issue involving antibiotic resistant bacteria like MRSA as well. (I've personally won this lottery ) In the case of hiv we know it naturally has a high rate of mutation. It's a tricky bastard. One way to reduce the amount of mutations created is by keeping the viral load as low as possible through HAART. The interesting question is if/how the presence of HAART drugs affect the rate or variation of mutation?

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Last year -- when I was very new to this and reading the literature heavily -- I noted that some of the life expectancy studies are based on assumptions regarding how long each successive therapy regime will be successful.

I was diagnosed in Dec and also remember coming across research where they were doing mathematical modeling based on current drug regimens. I also find it interesting but don't worry about it too much since it's based on current regimens. The next drug breakthrough could radically alter the models and research appears to be moving at a staggering pace on multiple fronts.

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Still, the line in the Bloomberg story saying that treatments fail within 3-4 years is obviously baloney

I understand the sensitivity around this statement but I wouldn't call it baloney. In mid January the labeling was changed for Complera's use on patients with an initial viral load over 100k because of a significantly higher rate of virologic failure within the first two years. (I started Complera on Jan 3rd with a vl of 240k and I'm not worried about it).

I wasn't trying to be alarmist with my lottery example and i apologize if it was a little too casual for this forum but it's not an inaccurate analogy. We do need to be equally careful though to assume that we can't develop resistance if we are adherent to our meds and undetectable. We can. Our 'odds' are just better if we're viraly suppressed.

Staying ahead of resistance is a numbers game. Newer drugs with higher efficacy and with lower side effects that help improve adherence will continue to improve these numbers in our favor.

Right now I'm more worried about retirement in 25 years than developing resistance

Definitely is and it's not just an issue for those with hiv. It's a global issue involving antibiotic resistant bacteria like MRSA as well. (I've personally won this lottery ) In the case of hiv we know it naturally has a high rate of mutation. It's a tricky bastard. One way to reduce the amount of mutations created is by keeping the viral load as low as possible through HAART. The interesting question is if/how the presence of HAART drugs affect the rate or variation of mutation? ote

I would imagine the probability of a mutation that renders the virus less fit is much much much higher than one that renders it more fit. However, what is happening during the reverse transcriptase step and what is integrated are TWO VERY DIFFERENT STEPS. What is integrated is the transcript that will be transcribed ALWAYS! However when things are reverse transcribed into DNA to new cells, most mutations like said above probably render the virus useless but the one that makes it more fit will make it to integration. You would think that with all the antibodies and the drugs in the bloodstream would prevent this copy from integrating preventing any resistance issues. Even having a resistant strain come into your system while on treatment should not be an issue because the antibodies should neutralize this strain. I think this is supported with evidence that reinfection is highly unlikely and there have been a few cases reported.

Remember folks, HIV inhabits reservoirs (brain/testes) that are beyond the reach of HAART. Even in those of us who have undetectable virus in our plasma still have actively replicating viruses within our bodies.

Rare mutations that increase the fitness (or reproductive success) of a virus may have either deleterious or rarely confer on it an advantage: Disadvantage 1) a mutation that increases virulence and kills off the host quickly would in time reduce the number of new infections (think the Ebola and Marburg viruses 2) a mutation in HIV that restores the host's ability to fight it (restoring IFN and apoptosis pathways) would also be disadvantageous.

Advantage: 1) drug resistance. Some folks (a minority) are just not "fit," enough to fight the virus, even with the aid of HAART. The viruses wins in the short run in this scenario but loses the war.

The bottom line, in my opinion, is viral persistence and the ongoing low-level chronic inflammation that we endure are more to be feared then the classic "superinfection," scenario-which has never materialized.

Advantage: 1) drug resistance. Some folks (a minority) are just not "fit," enough to fight the virus, even with the aid of HAART. The viruses wins in the short run in this scenario but loses the war.

Please show statistics. Please elaborate what a "minority" is. Please tell me about people, say infected within the last 10 years, on HAART at the appropriate time, and adherent - who were not "fit" and died of AIDS, cause all 2nd, 3rd, and salvage therapies useless. Hmmmm??

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“From each, according to his ability; to each, according to his need” 1875 K Marx

There are lies, damn lies and then there are statistics. Basic common sense here my friend. Antivirals and antibiotics only supplement our own immune responses to the various pathogens-they are not the cure all for everyone-nor has HAART alone eradicated the virus from anyone who has been infected any significant period of time.

I agree that perfect adherence and salvage therapies for those who have been diagnosed and treated early in their disease course will do a lot better in the long run than those of us who started with either nothing or AZT. Plus, studies have shown that the longer individuals stay virally suppressed the less likely they are to rebound. But I digress you wanted facts:

Bull Math Biol. 2007 Aug;69(6):2027-60. Epub 2007 Apr 21.Emergence of HIV-1 drug resistance during antiretroviral treatment.Rong L, Feng Z, Perelson AS.SourceDepartment of Mathematics, Purdue University, West Lafayette, IN 47907, USA.AbstractTreating HIV-infected patients with a combination of several antiretroviral drugs usually contributes to a substantial decline in viral load and an increase in CD4(+) T cells. However, continuing viral replication in the presence of drug therapy can lead to the emergence of drug-resistant virus variants, which subsequently results in incomplete viral suppression and a greater risk of disease progression. In this paper, we use a simple mathematical model to study the mechanism of the emergence of drug resistance during therapy. The model includes two viral strains: wild-type and drug-resistant. The wild-type strain can mutate and become drug-resistant during the process of reverse transcription. The reproductive ratio [Symbol: see text](0) for each strain is obtained and stability results of the steady states are given. We show that drug-resistant virus is more likely to arise when, in the presence of antiretroviral treatment, the reproductive ratios of both strains are close. The wild-type virus can be suppressed even when the reproductive ratio of this strain is greater than 1. A pharmacokinetic model including blood and cell compartments is employed to estimate the drug efficacies of both the wild-type and the drug-resistant strains. We investigate how time-varying drug efficacy (due to the drug dosing schedule and suboptimal adherence) affects the antiviral response, particularly the emergence of drug resistance. Simulation results suggest that perfect adherence to regimen protocol will well suppress the viral load of the wild-type strain while drug-resistant variants develop slowly. However, intermediate levels of adherence may result in the dominance of the drug-resistant virus several months after the initiation of therapy. When more doses of drugs are missed, the failure of suppression of the wild-type virus will be observed, accompanied by a relatively slow increase in the drug-resistant viral load.

Simulation results suggest that perfect adherence to regimen protocol will well suppress the viral load of the wild-type strain while drug-resistant variants develop slowly. However, intermediate levels of adherence may result in the dominance of the drug-resistant virus several months after the initiation of therapy. When more doses of drugs are missed, the failure of suppression of the wild-type virus will be observed, accompanied by a relatively slow increase in the drug-resistant viral load.

Still drumming my fingers, still waiting for statistics, field reports, actual studies of these few people who are are "just not "fit," enough to fight the virus, even with the aid of HAART."

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“From each, according to his ability; to each, according to his need” 1875 K Marx

I don't see how what Life2 is saying is controversial at all.. there have been numerous studies on low-level replication and also proof that some men have detectable VL in their semen, often with various mutations, even when undetectable in blood (yes I'll provide the link if requested). There ARE reservoirs that current meds don't touch, and that's just the way it is. However, in practice, staying undetectable does seem to render resistant mutations to a 'statistic' that doesn't cause us much worry. My doc also said I could probably stay on my regimen for the rest of my life, although I've just switched to Stribild for a few reasons, but not because of resistance. So there is no reason for hysteria but also no reason to get upset at someone simply responding to a query with accurate science.

Of course there is replication.Of course we should all adhere to our combos and keep fighting.

The pushback is about "one-size fits all articles" that make generalisations that make it seem like today's combos are failing in a few years. 2-3 years. NOT.

Or the other claim that some HIV+ are simply "un-fit" to stay undetectable and doomed to die of AIDS. With no explanation as to exactly who these treatment failures are and their backstories.....

This is 2013. Most of us got the message - stay adherent and be cautious but optimistic. Combos last for years now. Maybe decades. And new ones are on the way.

One-size fits all generalities about living well with HIV with casual throwaways to scary stories of those who don't manage to, are NOT constructive. As we are no longer a one-experience population....

TO BE CLEAR, i am not arguing that replication doesn't go on. I am not dying that some people experience treatment failure. But then what? Go on to another combo, and no more failure? Or failure. Then another failure. Then salvage failure..... Highly atypical, if adherence or some coinfection isn't the issue.

Since many of us have doctors who have told us to expect near normal life expectancy, we can assume that factored into that is the expectation of decades of viral suppression with effective haart. Maybe not the combo we are on on in 2013, when its 2035....

My only point is that these articles can be misread and lead to fear. That is all..

« Last Edit: August 21, 2013, 03:22:08 PM by mecch »

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“From each, according to his ability; to each, according to his need” 1875 K Marx